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Genetic counseling: Canavan Disease: Heterozygote Screening
Canavan Disease: Heterozygote Screening (2002) Contracting *What do you know about Canavan Disease? *What are your concerns? What do you hope to learn? Etiology and Natural History *Also called aspartoacylase deficiency or spongy degeneration of the brain *Caused by deficiency of aspartoacylase enzyme **Encoded by the gene ASPA **Found at chromosomal locus 17p13 **Responsible for hydrolyzing N-acetylaspartic acid (NAA) into aspartic acid and acetate **Expressed throughout body but mainly causes problems in central nervous system ***Build-up of NAA in brain ***Causes demyelinization leading to evidence of clinical symptoms *ASPA mutations **Over 30 different mutations have been identified **Three common mutations ***Account for 99% of disease causing alleles in Ashkenazi Jewish population and 55% of disease causing alleles in other populations ***Includes E285A, Y231X, and A305E ***Null mutations make no aspartoacylase, missense mutations make less active forms **No strong genotype-phenotype correlation but missense mutations not as severe as null mutations *Autosomal recessive inheritance **If both partners heterozygous for a mutation, each pregnancy has a 25% risk of resulting in a child with Canavan disease **Explanation of autosomal recessive inheritance Incidence and Carrier Frequency *Most reported cases are individuals of Ashkenazi Jewish descent **Carrier frequency about 1 in 40 to 1 in 60 **Incidence is about 1/6400 to 1/13,456 *Carrier frequency in general population is not known but assumed to be much lower than 1 in 40 (Maybe 1 in 300?) Clinical Features *Infants appear normal early in life *Developmental delay apparent at 3-5 months of age **Particularly delayed in motor skill development ***Can laugh and smile, reach for objects, and raise their head but may lose those skills ***Hypotonia, seizures, and poor eye contact develop by sixth month ***May not learn to sit, stand, walk, or talk **Can learn to interact socially but are sometimes irritable **Sleep disturbance and feeding difficulties begin as they get older **Macrocephaly *Life expectancy is variable **Varies from few years to the teens or beyond **Depends on clinical course of disease and medical care *Some studies have reported three forms **Neonatal, infantile, and late-onset **More recent studies show that disease usually begins in infancy with highly variable rate of disease progression *Neuropathology **CT or MRI in infancy may be normal **Later studies will show diffuse, symmetrical white matter changes and possible involvement of cerebellum and brainstem **Subcortical spongy degeneration **Distorted mitochondria Testing *Diagnostic testing **Increased levels of N-acetylaspartic acid (NAA) in urine ***Measure using gas chromatography-mass spectrometry ***Can also find elevated levels in blood and cerebrospinal fluid of older children **Aspartoacylase enzymatic activity ***Can be measured in cultured skin fibroblasts ****Affected patients have unmeasurable activity ****Carriers have about ½ normal activity ***Not detectable in white blood cells ***Cannot be used for prenatal diagnosis because normal enzyme levels very low in amniocytes and CVS tissue **Can do molecular testing to confirm diagnosis *Molecular testing **Primarily used for: ***Identify specific mutation in affected individuals ***Carrier testing of individuals of Ashenazi Jewish heritage ***Carrier testing for individuals with affected family members and their spouses ***Prenatal testing for at-risk pregnancies **Most labs use a two allele panel for testing ***Some labs use three allele panel ****Detects 99% of mutations in Ashkenazi Jewish population ****Detects only about 55% of mutations in other populations ***Testing for remaining mutations is on research basis only **Population Screening ***Initiated for Jewish individuals of reproductive age recommended by American College of Medical Genetics and American College of Obstetricians and Gynecologists ***Couples and partners who are carriers can be made aware of risks and status before having children **In the US and Canada, 27 labs offer testing ***Genetics and IVF Institute - Fairfax, Virginia ****Ashkenazi Jewish Recessive Disease panel *****Blood samples only (5-10 cc in lavender topped tube) *****Ship at room temperature *****Package to screen for most common mutations causing Tay-Sachs, Gaucher Disease, Canavan Disease, and Cystic Fibrosis *****Screens for 3 most common Canavan mutations *****No prenatal diagnosis *****Turn around time is 10-14 days ****Canavan Disease testing *****Blood samples same as above *****Amniotic fluid: ******<15 weeks send 2 confluent T25 flasks ******>15 weeks send 5 ml unspun fluid and keep backup cultures at our facility *****CVS send 5 mg cleaned CV tissue and maintain backup cultures *****Ship at ambient temperature *****Turn around time 7-10 days *****If carrier status of parents determined at another lab, must also send parental blood specimens as controls ***Laboratory Corporation of America - Research Triangle Park, NC ****Have primary testing and distribution center in Cincinnati ****Canavan Disease *****Blood sample (7 ml in lavender topped tube) *****Screens for only 2 mutations *****Send specimens at room temperature ****Jewish Heritage Profile 1 *****Blood sample (8 ml in lavender topped tube) *****Screens for mutations causing Canavan Disease, Cystic Fibrosis, Niemann-Pick, and Tay-Sachs *****Ship at room temperature *****Medicare and other carriers may not recognize this procedure as covered health care ****Jewish Heritage Profile II *****Blood sample same as above *****Screens for mutations causing Canavan Disease, Cystic Fibrosis, Fanconi Anemi (Type C), Gaucher, Niemann-Pick, and Tay-Sachs Disease *****Medicare and other carriers may not cover this test *****Not appropriate for non-Ashkenazi Jewish individuals ***Genzyme Genetics - Framingham, MA ****Ashkenazi Jewish Panal *****Blood sample (20 cc in purple topped tube) *****Tests for Cystic Fibrosis, Tay-Sachs, and Canavan and Gaucher Disease can be ordered in addition *****$375 for 3diseases, $480 for all 4 diseases *****Tests for 4 mutations in aspartoacylase gene *****Can also order each test individually, although very expensive *****Ship at room temperature via FedEx *****Turn around time approximately 10 days -Genzyme forms are in the red crate in the student room **Prenatal testing ***Molecular testing if specific ASPA mutation has been identified in both parents ***If one partner is a known carrier but status of the other partner is unknown, measure the level of NAA in amniotic fluid at 16-18 weeks **Research testing ***Supposedly available for mutations not tested for by clinical studies ***Duke University Medical Center does NOT offer research testing ***NYU School of Medicine may offer research testing ***Haemek Medical Center in Afula, Israel Management *No cure *Treatment focuses on support, nutrition, hydration, management of infectious diseases, and protection of the airway **Feeding tube if swallowing difficulties **Seizures treated with anticonvulsants *Physical therapy **Minimizes contractures **Maximize abilities and seating posture *Other therapies to enhance communication skills *Gene therapy **Studies with a mouse model are being used in gene therapy trials **Gene transfer to brain of two children with Canavan Disease ***Using non-viral vector ***Procedure well tolerated and some biochemical, radiological, and clinical changes may have been seen Differential Diagnosis *Alexander's Disease, Tay-Sachs disease, metachromatic leukodystrophy, and glutaric acidemia may have similar clinical symptoms *Laboratory or molecular genetic testing can be used to distinguish from these diseases *Spongy degeneration of the brain found in some viral disorders can also be distinguished by testing Psychosocial Issues *Past experiences with family members with Canavan Disease *DNA banking, particularly if an individual is diagnosed based on elevated NAA levels but molecular testing does not identify a mutation *Feelings about preimplantation genetic diagnosis and termination *Daily management of an affected family member *Financial pressures *Lifestyle changes necessary to care for an affected child *Guilt, depression Resources *Canavan Foundation :110 Riverside Drive #4F :New York, NY 10024 :Phone: 877-4-Canavan :Email: canavandisease@aol.com :www.canavanfoundation.org *National Foundation for Jewish Genetic Diseases, Inc :250 Park Ave, Ste 1000 :New York, NY 10177 :Phone: 212-371-1030 :Email: NFJGD@aol.com :www.nfjgd.org References *Genetics and IVF Institute. (2002). http://www.givf.com *GeneReviews. "Canavan Disease" (2002). http://www.geneclinics.org *GeneTests. "Canavan Disease" (2002). http://www.genetests.org *Genzyme Genetics. "Ashkenazi Jewish Panel" Patient literature. *Laboratory Corporation of America. (2002). http://www.labcorp.com *Online Mendelian Inheritance in Man. "Canavan Disease" (2002). http://www.ncbi.nih/gov *Scriver, CR, ed. The Metabolic and Molecular Bases of Inherited Disease. "Aspartoacylase Deficiency (Canavan Disease)" (2001):5799-580** Notes The information in this outline was last updated in 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling